IND-enabling preclinical development of a system for the multipurpose prevention of HIV and unintended pregnancy

支持 IND 的临床前开发系统，用于多用途预防艾滋病毒和意外怀孕

• 批准号: 9981612
• 负责人: Thomas J. Smith
• 金额: $ 100万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981612
• 关键词: AIDS prevention; Animals; Anti-Retroviral Agents; Antiviral Agents; Chemistry; Clinical; Clinical Trials; Collaborations; Contraceptive Agents; Contraceptive methods; Data; Development; Devices; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Engineering; Environment; FDA approved; Female of child bearing age; Formulation; Foundations; Fumarates; Goals; Grant; HIV; HIV Infections; HIV therapy; Half-Life; Hormones; Human; Infectious Pregnancy Complications; Integrase; Lead; Liquid substance; Macaca; Maintenance; Marketing; Mitochondria; Modeling; Nucleosides; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Prevention; Principal Investigator; Process; Publishing; RNA-Directed DNA Polymerase; Recording of previous events; Regimen; Reporting; Research; Research Personnel; Safety; Sheep; Small Business Innovation Research Grant; System; Technology; Tenofovir; Testing; Therapeutic Index; Time; Toxic effect; United States National Institutes of Health; Vagina; Vaginal Ring; Woman; Work; base; cervicovaginal; commercialization; drug development; emtricitabine; experience; first-in-human; in vivo; inhibitor/antagonist; innovation; microbiome; novel; pre-clinical; pre-exposure prophylaxis; preclinical development; preclinical efficacy; product development; programs; response; scaffold; truvada; unintended pregnancy; uptake; vaginal microbiome

SUMMARY (changes are underlined) The broad, long-term goal of this research program is to develop an intravaginal multipurpose prevention technology (MPT) product to provide HIV pre-exposure prophylaxis (PrEP) and contraception to women in the developing world. MPT is a high priority for the NIH, the WHO and for leading NGOs. Our strategy is based on delivering the best-in-class HIV PrEP candidates using our proprietary and novel “intravaginal beads” in conjunction with FDA-approved contraceptive IVRs. Truvada® (TDF-FTC combination) is the only FDA-approved drug product for HIV PrEP. However, recent studies have shown NRTI-associated vaginal mitochondrial toxicity, including the data found in our Phase I SBIR efforts. In our original Phase II SBIR (Jan ’18) submission, we presented pre-clinical results for a TDF- FTC bead formulation, and a proposal to adapt the bead technology to the cabotegravir (CBT)-rilpivirine (RPV) combination. At that time, the FDA had just approved Juluca®, which till date remains to be the only two-drug (dolutegravir [DTG] + rilpivirine) medication for HIV treatment. In the past twelve months, several post- marketing studies of Juluca® have been published showing enhanced safety and efficacy. Additionally, the DTG-RPV combination can also act as PrEP agents at very low levels and has a long half-life with lesser known potential for mitochondrial toxicity than NRTIs. On the other hand, the CBT-RPV combination, although in late-stage clinical trials, is not yet approved by the regulatory agencies. Hence, given the significant regulatory and scientific advantages of DTG-RPV drug combination over CBT-RPV, we shifted our product development focus towards the former. One of the main concerns with our original submission was the lack of preliminary data. In response, we resubmit this application with pre-clinical results for the proposed drug selection. Briefly, a 1-month pharmacokinetics (PK) study was performed in a sheep model to evaluate feasibility of the DTG-RPV beads when delivered in combination with a contraceptive IVR (NuvaRing®). The beads demonstrated an average in vivo release of 2.4 mg/d DTG and 0.6 mg/d RPV. The resulting average cervicovaginal fluid (CVF) levels were 537 ng/ml DTG and 807 ng/ml RPV suggesting sustained delivery at concentrations greater than their respective EC50 levels. The drug loading capacity of these beads allows us to formulate them as 3-month beads making it feasible for use in combination with either a monthly Nuvaring® (in this scenario, one bead will be used for three consecutive monthly IVRs over a 3-month period) or a yearly Annovera® (here, four beads will be required for one IVR over a 12-month period), depending on the user’s choice. This Phase II SBIR resubmission proposes the following revised plan: In Year 1, we will manufacture pre- clinical batches of DTG and RPV beads; and conduct IND-enabling safety/PK studies in sheep and macaques. In Year 2, we will test the formulation for efficacy in a macaque model. Finally, we will perform IND-enabling chemistry, manufacturing and controls (CMC) activities for the lead formulation to submit an IND. We have been granted 13 IND approvals, and the only sustained release antiviral drug delivery device ever approved by the FDA (the Vitrasert®) was developed by the Principal Investigator of this proposal. Successful completion of the work described in this proposal will allow human testing of this novel intravaginal MPT.

摘要（变化是下划线的） 该研究计划的广泛长期目标是开发经动式多功能预防 技术（MPT）产品可为妇女提供艾滋病毒预防前预防（PREP）和避孕 发展中国家。 MPT是NIH，WHO和领导非政府组织的重中之重。我们的策略是基于 使用我们的专有和新颖的“阴道内珠”提供一流的艾滋病毒准备候选者 与FDA批准的避孕IVR的联系。 Truvada®（TDF-FTC组合）是唯一用于HIV Prep的FDA批准药物。但是，最近 研究表明，NRTI相关的阴道线粒体毒性，包括在我们I期中发现的数据 SBIR努力。在我们最初的II阶段SBIR（18）提交中，我们提出了TDF-的临床前结果 FTC珠子公式，以及将珠子技术调整到Cabotegravir（CBT）-Rilpivirine（RPV）的提议 组合。当时，FDA刚刚批准了Juluca®，直到迄今为止，这仍然是唯一的两次药物 （Dolutegravir [DTG] + Rilpivirine）用于HIV治疗的药物。在过去的十二个月中，几个 Juluca®的营销研究已发表，显示出增强的安全性和有效性。另外， DTG-RPV组合也可以充当非常低水平的预备剂，并且具有较长的半衰期，较少 已知的线粒体毒性潜力比NRTIS。另一方面，CBT-RPV组合，尽管 在后期临床试验中，尚未获得监管机构的批准。因此，鉴于重要 DTG-RPV药物组合比CBT-RPV的监管和科学优势，我们转移了产品 发展专注于前者。 我们最初提交的主要问题之一是缺乏初步数据。作为回应，我们 重新提交此应用，并以临床前的结果进行拟议的药物选择。简而言之，一个月 在绵羊模型中进行了药代动力学（PK）研究，以评估DTG-RPV珠的可行性 当与避孕IVR（Nuvaring®）结合使用时。珠子平均显示 2.4 mg/d DTG和0.6 mg/d RPV的体内释放。由此产生的平均子宫颈液（CVF）水平为 537 ng/ml DTG和807 ng/ml RPV表明，浓度大于其浓度的持续交付 EC50水平。这些珠的药物负载能力使我们能够将它们作为3个月 珠子使其可与任何一个每月的nuvaring®相结合使用（在这种情况下，一个珠子将 在3个月的时间内连续三个每月IVR）或每年的Annovera®（在这里，四个珠子 根据用户的选择，将需要一个IVR一个IVR）。 该II期SBIR重新提议提案以下修订计划：在第一年，我们将制造前 DTG和RPV珠的临床批次；并在绵羊和猕猴中进行辅助安全/PK研究。 在第二年，我们将测试猕猴模型中效率的公式。最后，我们将执行indshabbling 用于提交IND的主要公式的化学，制造和控制（CMC）活动。 我们获得了13个IND批准，这是有史以来唯一持续释放的抗病毒药物输送装置 该提案的首席研究员开发了FDA（VITRASERT®）批准。成功的 该提案中描述的工作的完成将允许对这一新型阴道内MPT进行人体测试。